Aspartame Risk Assessment Food Safety Analysis Exercise

1. Aspartame Risk AssessmentFood Safety Analysis Exercise Charles Yoe, Ph.D. College of Notre Dame of Maryland

2. Food Additives • Chemicals added to food in small amounts • Direct additives • Indirect additives

3. Direct Additives • Deliberately added • Make food look and taste better • Maintain or improve nutritive value • Maintain freshness • Help processing or preparation • Help preserve food • Intense sweeteners

4. Indirect Additives • Enter food incidentally during • Handling • Processing (equipment) • Packaging

5. Is aspartame safe?

6. Risk Analysis Risk Management Risk Assessment Risk Communication

7. Why Do Risk Analysis? • To improve decisions • To help assure a safe domestic food supply • It’s essential for international trade • To enable industry to innovate • Because we have to

8. Risk Assessment • What can go wrong? • How can it happen? • How likely is it? • What are the consequences?

9. Risk Management • What question(s) do we want risk assessment to answer? • What can be done to reduce the impact of the risk described? • What can be done to reduce the likelihood of the risk described? • What are the trade-offs of the available options? • What is the best way to address the described risk?

10. Risk Communication • With whom do you communicate? • How do you get both the information you need and the information others have? • How do you convey the information you want to communicate? • When do you communicate?

11. Food Additive Safety Analysis Amount of substance consumed Safe amount of substance >1 => not safe = 1 => safe < 1 => safe

12. Food Safety Assessment Not True Risk Assessment • Food safety assessment procedures are widely accepted globally • They do not assess the risks of an additive • They identify a level considered safe for the population • Risks are managed rather than explicitly assessed

13. Does It Answer the Questions? What can go wrong? Cancer How can it happen? Uncertain mechanism How likely is it? Unknown What are consequences? Possible death

14. It Does Answer • What can be done to reduce the impact of the risk? • Limit intake • What can be done to reduce the likelihood of the risk? • Limit intake • Food safety assessment is risk management not risk assessment

15. What Do We Know About Aspartame? • Why do we care about it? • How do we find out about it? • Where do we go? • Literature • Government agencies • Scientific organizations • Academe • Other

16. Table-top sweeteners Instant beverages Carbonated soft drinks Juices Ice tea Dairy products Jams, marmalades Candies Cider,pickles, sauces Fish & fruit preservatives Chewing gums Multivitamins Ice Cream Puddings and jellies Chocolate Toothpaste, mouthwash Pharmaceuticals Aspartame Uses

17. Composition & Decomposition • Aspartame molecule consists of 3 substances linked together • aspartic acid • phenylalanine • methanol • When stored a long time or exposed to high temperatures it can break down • diketopiperazine (DKP)

18. Aspartame Concerns • Cancer studies • Animal tests • Special Groups in the Population • children, diabetics, people on weight reduction diets, lactating women, people who carry the gene for phenylketonuria • Behavioral Effects • mood, behavior • Possible Adverse Reactions • headaches, rashes, menstrual irregularities, other

19. History • Discovered 1965 • Originally approved by FDA in 1974 • Clearance temporarily postponed--2 objections • Evaluated by JECFA in 1980 & 81 • Approved for dry food use in US 1981 • Scientific Committee for Food 1985 • UK Committee on Toxicity of Chemicals in Food, Consumer Products & Environment

20. How is aspartame regulated in your country now?

21. Paracelsus • “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” • No food substance is unequivocally safe or unsafe • Safety depends on amount in diet

22. Food Safety • Safe: Experts’ best judgment about the level of exposure to a substance that has reasonable certainty of no harm to humans under the intended conditions of its use. • Terms • Acceptable Daily Intake (ADI) • Reference Dose

23. Food Safety Assessment • Calculate Estimated Daily Intake (EDI) of substance • Undertake toxicity studies of substance if needed • Determine “No Observed Adverse Effect Level” (NOAEL) • Select safety factor or uncertainty factor to extrapolate results from animals to humans • Calculate Acceptable Daily Intake (ADI) • Compare EDI and ADI

24. Estimated Daily Intake (EDI) • Information on concentration of substance in food from chemical analyses, data on food processing, agency records, and so on. • Consumer surveys estimate portion sizes and frequency of eating foods potentially containing substance (aspartame). • Assumptions

25. EDI • How can you get EDI information? • What are the advantages/disadvantages of existing studies? • Whose EDI do you want? • All people or just consumers of substance? • Median consumer or consumer of large quantities? • Young? Old? Immuno-compromised?

26. Intake Survey Types • Recall • Diary • Duration

27. Design a Survey • What do you need to be concerned about? • Population studied • Measurements necessary • Duration of study • Data analysis • Data interpretation

28. Population Studied • General population • All • Consumers • High intake groups • Special groups • Children • Pregnant women • Diabetics

29. Measurements Necessary • Quantitative intake of foods & beverages • Special product types (e.g. low calorie) • Specific brands • Sweetener concentration differences

30. Duration of Study • Human intake equivalent to safety study duration • Subchronic (90 days) • Chronic (lifetime) • Actual studies limited • 1-day studies common • 7-day average a good compromise

31. Data Analysis • % consumers in study population • Source of intake, patterns of use • Average intake consumers-only • Mean, median and extreme consumers • High consumers • 90th, 95th or 97.5th percentile

32. Level of Consumption • How do we find out how much is in diet? • Surveys and Assumptions • If Aspartame replaces all sucrose in US diet • average is 8.3 mg/kg/day • If Aspartame replaces all carbohydrates • average is 25 mg/kg/day • 99th percentile of Aspartame consumption • 34 mg/kg/day

33. Level of Consumption • Monitor consumption • 90th percentile 1984-89 • 1.6 to 2.3 mg/kg/day • 99th percentile • 5.8 to 6.5 mg/kg/day • 99th percentile for all children US • 3.0 to 8.3 mg/kg/day • 95th percentile for children Canada • 5.7 to 12.3 mg/kg/day

34. Level of Consumption • 99th percentile diabetics US • 8.0 to 8.3 mg/kg/day • 95th percentile diabetics Canada • less than 15 mg/kg/day • How do these relate to the ADI?

35. EDI • Using these data and what you know • Identify an EDI • Explain your choice • Strengths • Weaknesses

36. Toxicological Aspartame Data • Over 100 studies • Acute toxicity • Sub-chronic toxicity • Chronic toxicity • Carcinogenicity • Genotoxicity • Reproductive toxicity, teratogenicity, fertility • Special developmental studies • Pharmacological studies

37. NOAEL • No-observed-adverse-effects-level or No-observed-effects-level (NOEL) • Biggest dose of chemical that produces no toxicity • In toxicology, the highest dose at which no adverse effect is observed

38. Animal Studies • Relatively high dose to relatively few animals • Absence of data in low dose region • Which mathematical model best approximates dose-response in low dose region • Fit data that exists • Linear extrapolation to zero from fitted curve or 95% confidence interval

39. Dose Response Linear Extrapolation Upper Confidence Limit Actual Data Excess Tumor Rate Alternative Extrapolations Estimated Dose Response Linear Extrapolation Dosage Experimental Range

40. Low Dose Response • Two extrapolation problems • From animals to humans • From high dose to low dose • Many mathematical models possible • Alternative approach is to use safety factors or uncertainty factors

41. From NOAEL to ADI • The NOAEL is an estimate for animals • Need to get to humans

42. ADI • Maximum acceptable daily intake (ADI) • ADI is not an absolute limit that can never be exceeded • ADI is an estimate of the amount of an additive that can be consumed daily for a lifetime without adverse effects • Used to estimate population safety not individual safety

43. ADI Rules of Thumb • Intakes predicted using conservative budgets present no problem—actual intake data not necessary • Intake data needed when intake could be close to ADI

44. Safety/Uncertainty Factors • Multiply all factors that pertain to food safety assessment for overall safety factor • ADI is the NOAEL divided by the safety factor NOAEL Safety Factor

45. Safety/Uncertainty Factors • 10 for extrapolation of NOAEL’s obtained from chronic toxicity studies in animals to humans • 10 for extrapolation of NOAEL’s obtained from subchronic toxicity studies in animals to humans • 10 for extrapolation of NOAEL’s for severe irreversible endpoints from reproductive or developmental toxicity studies to humans • 10 for sensitive populations • 10 for children • 10 for variability in the population

46. Safety Factor • Identify relevant factors • Justify your choice • Calculate safety factor • Using previous NOAEL calculate an ADI

47. Acute Toxicity • Aspartame and DKP • Oral LD50 > 5000mg/kg in mouse, rat, & rabbit • NOAEL up to 10,000 mg/kg

48. Chronic/Sub Chronic Studies NOAEL • Aspartame • Mouse ===> 4000 mg/kg/day • Rat======> 2000 mg/kg/day • Dog=====> 1000 mg/kg/day • Monkey==> 1000 mg/kg/day • DKP • Mouse====> 1000 mg/kg/day • Rat======> 750 mg/kg/day

49. How Is This Done? • Must every nation do its own toxicology? • This is same for all • Use what is available • The Internet is a good source of these data • You can begin your search at this web site

50. Use What’s Available • Food Safety Risk Analysis Clearinghouse • www.foodriskclearinghouse.umd.edu • Joint Expert Committee on Food Additives • http://jecfa.ilsi.org • TOXNET • http://toxnet.nlm.nih.gov